The present invention relates to new biphenyl and biphenyl-analogous compounds, their preparation and use as pharmaceutical compositions, as integrin antagonists and in particular for the production of pharmaceutical compositions for the treatment and prophylaxis of cancer, arteriosclerosis, restenosis, osteolytic disorders such as osteoporosis, rheumatoid arthritis and ophthalmic diseases.
Integrins are heterodimeric transmembrane proteins found on the surface of cells, which play an important part in the adhesion of the cells to an extracellular matrix. They recognize extracellular glycoproteins such as fibronectin or vitronectin on the extracellular matrix by means of the RGD sequence occurring in these proteins (RGD is the single letter code for the amino acid sequence arginine-glycine-aspartate).
In general, integrins such as, for example, the vitronectin receptor, which is also called the xcex1vxcex23 receptor, or alternatively the xcex1vxcex25 receptor or the GpIIb/IIIa receptor play an important part in biological processes such as cell migration and cell-matrix adhesion and thus in diseases in which these processes are crucial steps. Cancer, osteoporosis, arteriosclerosis, restenosis (reoccurrence of stenosis after percutaneous transluminal angioplasty) and opthalmia may be mentioned by way of example.
The xcex1vxcex23 receptor occurs, for example, in large amounts on growing endothelial cells and makes possible their adhesion to an extracellular matrix. Thus the xcex1vxcex23 receptor plays an important part in angiogenesis, i.e. the formation of new blood vessels, which is a crucial prerequisite for tumor growth and metastasis formation in carcinoses. Furthermore, it is also responsible for the interaction between osteoclasts, i.e. cells resorbing mineralized tissue, and the bone structure. The first step in the degradation of bone tissue consists in the adhesion of osteoclasts to the bone. This cell-matrix interaction takes place via the xcex1vxcex23 receptor, which is why the corresponding integrin plays an important part in this process. Osteolytic diseases such as osteoporosis are induced by an inequilibrium between bone formation and bone destruction, i.e. the resorption of bone material caused by accumulation of osteoclasts predominates.
It was possible to show that the blockage of the abovementioned receptors is an important starting point for the treatment of disorders of this type. If the adhesion of growing endothelial cells to an extracellular matrix is suppressed by blocking their appropriate integrin receptors, for example, by a cyclic peptide or a monoclonal antibody, the endothelial cells die. Therefore angiogenesis does not occur, which leads to a cessation or resolution of the tumor growth (cf., for example, Brooks et al., Cell, Volume 79, 1157-1164, 1994).
Moreover, the invasive properties of tumor cells and thus their capability for metastasis formation are markedly decreased if their xcex1vxcex23 receptor is blocked by an antibody (Brooks et al., J. Clin. Invest., Volume 96, 1815, 1995).
The degradation of bone tissue can be suppressed by blockage of the xcex1vxcex23 receptors of the osteoclasts, since these are then unable to accumulate on the bone in order to absorb its substance (WO 98/18461, p. 1, 1.24 to p. 2,1.13).
By means of the blockage of the xcex1vxcex23 receptor on cells of the smooth aorta vascular musculature with the aid of integrin receptor antagonists, the migration of these cells into the neointima and thus angioplasty leading to arteriosclerosis and restenosis can be suppress ed (Brown et al., Cardiovascular Res., Volume 28, 1815, 1994).
In recent years, compounds have therefore been sought which act as a ntagonists of integrin receptors. For example, WO 98/00395 discloses the para-substituted phenylalanine derivative (I), which shows an IC50 value of 0.13 nM in an xcex1vxcex23 receptor assay and an IC50 value of 0.16 nM in an xcex1vxcex25 receptor assay: 
The abovementioned compound (I) has a guanidine unit, by means of which the oral availability is limited on account of the relatively rapid clearance rate of the compound in the digestive tract. Thus the compound (II), for example, is preferably administered parenterally (cf. WO 98/00395, p. 25, 1.31-32).
Furthermore, WO 98/18461, for example, discloses naphthyl compounds such as (II), which have an IC50 value in the range from 0.4 to 110 nM against the xcex1vxcex23 receptor in an SPA assay: 
Biphenyl nuclei are present in numerous pharmaceutical compositions. Experiments carried out until now to establish integrin antagonists having a biphenyl nucleus only led, however, to compounds having relatively poor activity. Thus, in addition to numerous substances included by a general formula, WO 94/12181 actually describes the biphenyl compounds (III) as antagonists of the GpIIb/IIIa receptor. The use of these compounds as xcex1vxcex23 or xcex1vxcex25 receptor antagonists is not described: 
The biphenyl compounds such as (IV) prepared by B. R. Neustadt et al. exhibit activity as xcex1vxcex23 receptor antagonists which is far below that of known integrin antagonists, which is why they are not suitable lead structures according to this document (Bioorg. Med. Chem. Lett. 8, 2395, 1998, in particular p. 2398, second paragraph): 
It was the object of the present invention to develop compounds which exhibit a high activity as integrin antagonists and in particular against the xcex1vxcex23 and/or the xcex1vxcex25 receptor.
The present object is achieved according to the invention by the substituted biphenyl compounds defined below. In particular, it has emerged that the biphenyl compounds according to the invention have a very high activity as integrin antagonists, especially against the xcex1vxcex23 and/or the xcex1vxcex23 receptor.
The present invention relates to compounds of the general formula (1) 
wherein
R1 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x2, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22;
R2xe2x80x2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R2xe2x80x3 is a substituted or unsubstituted alkyl, alkenyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
U is a direct bond or a substituted or unsubstituted alkylene group;
V is a substituted or unsubstituted alkylene group, xe2x80x94NR2xe2x80x2COxe2x80x94 or xe2x80x94NR2xe2x80x2SO2xe2x80x94;
A and B are each independently of one another a 1,3- or 1,4-bridging phenylene group or a 2,4- or 2,5-bridging thienylene group each of which may optionally have additional substituents,
W is a direct bond or a substituted or unsubstituted alkylene group;
C is a direct bond or 
R3 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R4, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R3 is bonded, and can be saturated or unsaturated and/or can contain further heteroatoms;
R4 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R3, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is CHNO2, CHCN, O, N or S;
Y is a direct bond or an optionally substituted alkylene or alkine group;
R5 is absent, or is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COR5xe2x80x2, xe2x80x94COOR5xe2x80x2, or is connected to one of R3, Y, R4 or R6, if present, with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
R5xe2x80x2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue which can be saturated or unsaturated and/or can contain further heteroatoms;
R6 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl or arylcarbonyl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R3, R4, Y or R5, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
with the proviso that if A is a phenylene group and V is xe2x80x94NR2xe2x80x2COxe2x80x94 or xe2x80x94NR2xe2x80x2SO2xe2x80x94, C is not a direct bond and X is not N; and their physiologically acceptable salts and stereoisomers.
If a certain variable substituent is present more than once in a general formula (e.g. R2xe2x80x2 in xe2x80x94NR2xe2x80x2COOR2xe2x80x2) the meaning for each substituent may be chosen independently from the others out of the list given in the respective definition.
According to a preferred embodiment, the present invention relates to compounds of the general formula (1), where
R1 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x2, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22;
R2xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclpentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R2xe2x80x3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, 1,1,1-trifluorobutyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, 4-ethylphenyl, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-trifluoro-phenyl, 2-trifluoromethoxy-4-bromo-phenyl, 2-fluoro-4-trifluoromethylphenyl, 8-quinolinyl or a group of the formula 
U is a direct bond,
V is an optionally substituted C1-5-alkylene group;
A is a 1,3- or 1,4-bridging phenylene group which is unsubstituted or carries at least one alkoxy or halogeno residue;
B is a 1,3- or 1,4-bridging phenylene group which is unsubstituted or carries at least one alkyl residue;
W is a direct bond or an optionally substituted C1-4-alkylene group;
C is a direct bond or 
R3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, 2-methylbutyl, isopentyl, neopentyl, hexyl, C1-4-perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, C1-2-perfluoroalkyl-C1-4-alkyl, 
xe2x80x83wherein Z is hydrogen, CH3, xe2x80x94NO2 or xe2x80x94NH2, or R3 is connected to one of R4, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R3 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
R4 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methyl-propyl, isobutyl, t-butyl, pentyl, 2-methyl-butyl, isopentyl, neopentyl, hexyl, C1-4-perfluoralkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, C1-2-perfluoralkyl-C1-4-alkyl, one of the residues (a1) to (a51) or is connected to one of R3, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is CHNO2, CHCN, O, N or S;
Y is a direct bond or a substituted or unsubstituted methylene or methine group;
R5 is absent, or is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COR5xe2x80x2, xe2x80x94COOR5xe2x80x2 or is connected to one of R3, Y, R4 or R6, if present, with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
R5xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, hexyl, C1-4-perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, C1-2-perfluoroalkyl-C1-4-alkyl, one of the residues (a1) to (a51) or is connected to one of R3, Y, R4 or R5, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms.
Particularly preferred compounds of the general formula (I) according to this embodiment are those in which
R2 is xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x2, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22;
R2xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R2xe2x80x3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, 1,1,1-trifluorobutyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, 4-ethylphenyl, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-trifluoro-phenyl, 2-trifluoromethoxy-4-bromo-phenyl, 2-fluoro-4-trifluoromethylphenyl, 8-quinolinyl or a group of the formula 
xe2x80x83and the other substituents are as defined above.
Particularly preferred compounds of the formula (1) are in this case those in which
R2 is xe2x80x94NR2xe2x80x2SO2R2xe2x80x3 or xe2x80x94NR2xe2x80x2COOR2;
R2xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R2xe2x80x3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, 1,1,1-trifluorobutyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, 4-ethylphenyl, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-trifluorphenyl, 2-trifluoromethoxy-4-bromophenyl, 2-fluoro-4-trifluoromethylphenyl, 8-quinolinyl, a group of the formula 
A is a 1,3- or 1,4-bridging phenylene group optionally substituted with a methoxy or up to 2 fluororesidues;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
C is a direct bond or 
R5 is absent, xe2x80x94NO2, xe2x80x94CN, or is connected to one of R3, Y, R4 or R6, if present, with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
and the other substituents are as defined above.
Additionally preferred compounds of the general formula (1) according to the present embodiment are those in which
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond,
V is xe2x80x94CHR7xe2x80x94 or xe2x80x94CHR7(CH2)1-4xe2x80x94;
R7 is xe2x80x94NR7xe2x80x2SO2R7xe2x80x3, xe2x80x94NR7xe2x80x2COOR7xe2x80x2, xe2x80x94NR7xe2x80x2COR7xe2x80x2, xe2x80x94NR7xe2x80x2CONR7xe2x80x22 or xe2x80x94NR7xe2x80x2CSNR7xe2x80x22;
R7xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R7xe2x80x3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, or 8-quinolinyl,
and the other substituents are as defined above.
Particularly preferred compounds of the general formula (1) in this case are those in which
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond;
V is xe2x80x94CHR7xe2x80x94;
R7 is xe2x80x94NR7xe2x80x2SO2R7xe2x80x3 or xe2x80x94NR7xe2x80x2COOR7xe2x80x3;
R7xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R7xe2x80x3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butyphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, or 8-quinolinyl,
A is a 1,3- or 1,4-bridging phenylene group optionally substituted with a methoxy or up to 2 fluoro residnes;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
C is a direct bond or 
W is a direct bond or a xe2x80x94CH2-group
X is O or S;
Y is a direct bond
R5 is absent
and the other substituents are as defined above.
Additionally preferred compounds of the general formula (1) according to the present embodiment are those in which
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond,
V is a C1-5-alkylene group which is optionally substituted by one or more residues R7 which are selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl, a substituted derivative or a saturated or unsaturated, optionally substituted heterocyclic analog thereof, an optionally substituted alkenyl residue or an optionally substituted alkinyl residue;
and the other substituents are as defined above.
Particularly preferred compounds of the general formula (1) in this case are those in which
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond,
V is xe2x80x94CHR7xe2x80x94;
R7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
A is a 1,3- or 1,4-bridging phenylene group optionally substituted with a methoxy or up to 2 fluoro residues
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
C is a direct bond or 
W is a direct bond or a xe2x80x94CH2xe2x80x94group
X ist O or S;
Y is a direct bond
R5 is absent
and the other substituents are as defined above.
According to yet another preferred embodiment, the present invention relates to compounds of the general formula (1), in which
R1 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof,
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl, phenylethyl, a substituted derivative or a saturated or unsaturated, optionally substituted heterocyclic analog thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue;
U is a direct bond or an optionally substituted C1-3-alkylene group;
V is xe2x80x94NR8COxe2x80x94 or xe2x80x94NR8SO2xe2x80x94;
R8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl, phenylethyl, phenylpropyl, phenoxyethyl or a substituted derivative thereof;
A is a 1,3- or 1,4-bridging phenylene group or a 2,4- or 2,5-bridging thienylene group which are unsubstituted or have at least one alkoxy or halogeno residue;
B is a 1,3- or 1,4-bridging phenylene group which is unsubstituted or has at least one alkyl residue;
W is a direct bond or an optionally substituted C1-3-alkylene group;
C is 
R3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, 2-methylbutyl, isopentyl, neopentyl, hexyl, C1-4-perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, C1-2-perfluoroalkyl-C1-4-alkyl, one of the residues (a1) to (a51) or is connected to one of R4, Y or R6, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R3 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
R4 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methyl-propyl, isobutyl, t-butyl, pentyl, 2-methyl-butyl, isopentyl, neopentyl, hexyl, C1-4-perfluoralkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, C1-2-perfluoralkyl-C1-4-alkyl, one of the residues (a1) to (a51) or is connected to one of R3, Y or R6, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is CHNO2, CHCN, O or S;
Y is a direct bond or a substituted or unsubstituted methylene or methine group;
R5 is absent;
R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, hexyl, C1-4-perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, allyl, propinyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, C1-2-perfluoroalkyl-C1-4-alkyl, one of the residues (a1) to (a51) or is connected to one of R3, Y or R4, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms.
Particularly preferred compounds of the general formula (1) according to this embodiment are those in which
U is a direct bond or xe2x80x94CHR7xe2x80x94;
R7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue or pyridyl;
A is a 1,3- or 1,4-bridging phenylene group optionally substituted with a methoxy group or up to 2 fluoro residues;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
W is a direct bond or a xe2x80x94CH2-group;
C is 
X ist O or S;
Y is a direct bond
R5 is absent
and the other substituents are as defined above.
Another group of particularly preferred compounds of the general formula (1) according to this embodiment are those in which
A is a 2,4- or 2,5-bridging thienylene group which ist unsubstituted or has at least one alkoxy residue and the other substituents are as defined above.
Further embodiments of the invention are described below.
The present invention furthermore relates to compounds of the general formula (1) 
wherein
R1 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x3, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22;
R2xe2x80x2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R2xe2x80x3 is a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
U is a direct bond or a substituted or unsubstituted alkylene group;
V is a substituted or unsubstituted alkylene group, xe2x80x94NR2xe2x80x2COxe2x80x94 or xe2x80x94NR2xe2x80x2SO2xe2x80x94;
A and B are each independently of one another a 1,3- or 1,4-bridging, optionally additionally substituted phenylene group;
W is a direct bond or a substituted or unsubstituted alkylene group;
C is a direct bond or 
R3 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R4, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R3 is bonded, and can be saturated or unsaturated and/or can contain further heteroatoms;
R4 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R3, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is CHNO2, CHCN, O, N or S;
Y is a direct bond or an optionally substituted alkylene or alkine group;
R5 is absent, or is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COR5xe2x80x2, xe2x80x94COOR5xe2x80x2, or is connected to one of R3, Y, R4 or R6, if present, with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
R5xe2x80x2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue which can be saturated or unsaturated and/or can contain further heteroatoms;
R6 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R3, R4, Y or R5, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
with the proviso that if V is xe2x80x94NR2xe2x80x2COxe2x80x94 or xe2x80x94NR2xe2x80x2SO2xe2x80x94, C is not a direct bond and X is not N; and their physiologically acceptable salts and stereoisomers.
According to a preferred embodiment, the present invention relates to compounds of the general formula (1), where
R1 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x3, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22;
R2xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclpentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R2xe2x80x3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, or 8-quinolinyl,
U is a direct bond,
V is an optionally substituted C1-5-alkylene group;
A is a 1,3- or 1,4-bridging phenylene group which is unsubstituted or carries at least one alkoxy residue;
B is a 1,3- or 1,4-bridging phenylene group which is unsubstituted or carries at least one alkyl residue;
W is a direct bond or an optionally substituted C1-4-alkylene group;
C is a direct bond or 
R3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, 
xe2x80x83or is connected to one of R4, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R3 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
R4 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, one of the residues (a1) to (a29) or is connected to one of R3, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is CHNO2, CHCN, O, N or S;
Y is a direct bond or a substituted or unsubstituted methylene or methine group;
R5 is absent, or is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COR5xe2x80x2, xe2x80x94COOR5xe2x80x2 or is connected to one of R3, Y, R4 or R6, if present, with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
R5xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, one of the residues (a1) to (a29) or is connected to one of R3, Y, R4or R5, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms.
Particularly preferred compounds of the general formula (I) according to this embodiment are those in which
R2 is xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x3, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22;
R2xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R2xe2x80x3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, or 8-quinolinyl,
and the other substituents are as defined above.
Particularly preferred compounds of the formula (1) are in this case those in which
R2 is xe2x80x94NR2xe2x80x2SO2R2xe2x80x3 or xe2x80x94NR2xe2x80x2COOR2xe2x80x3;
R2xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R2xe2x80x3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, or 8-quinolinyl,
A is an optionally methoxy-substituted 1,3- or 1,4-bridging phenylene group;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
C is 
W is a direct bond;
X is O or S;
Y is a direct bond;
R5 is absent;
and the other substituents are as defined above.
Additionally preferred compounds of the general formula (1) according to the present embodiment are those in which
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond,
V is xe2x80x94CHR7xe2x80x94 or xe2x80x94CHR7(CH2)1-4xe2x80x94;
R7 is xe2x80x94NR7xe2x80x2SO2R7xe2x80x3, xe2x80x94NR7xe2x80x2COOR7xe2x80x3, xe2x80x94NR7xe2x80x2COR7xe2x80x2, xe2x80x94NR7xe2x80x2CONR7xe2x80x22 or xe2x80x94NR7xe2x80x2CSNR7xe2x80x22;
R7xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R7xe2x80x3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, or 8-quinolinyl,
and the other substituents are as defined above.
Particularly preferred compounds of the general formula (1) in this case are those in which
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond;
V is xe2x80x94CHR7xe2x80x94;
R7 is xe2x80x94NR7xe2x80x2SO2R7xe2x80x3 or xe2x80x94NR7xe2x80x2COOR7xe2x80x3;
R7xe2x80x2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl;
R7xe2x80x3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butyphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, or 8-quinolinyl,
A is an optionally methoxy-substituted 1,3- or 1,4-bridging phenylene group;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
C is 
W is a direct bond;
X is O or S;
Y is a direct bond;
R5 is absent;
and the other substituents are as defined above.
Additionally preferred compounds of the general formula (1) according to the present embodiment are those in which
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond,
V is a C1-5-alkylene group which is optionally substituted by one or more residues R7 which are selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl, a substituted derivative or a saturated or unsaturated, optionally substituted heterocyclic analog thereof, an optionally substituted alkenyl residue or an optionally substituted alkinyl residue;
and the other substituents are as defined above.
Particularly preferred compounds of the general formula (1) in this case are those in which
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
U is a direct bond,
V is xe2x80x94CHR7xe2x80x94;
R7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue,
A is an optionally methoxy-substituted 1,3- or 1,4-bridging phenylene group;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
C is 
W is a direct bond;
X is O or S;
Y is a direct bond;
R5 is absent;
and the other substituents are as defined above.
According to yet another preferred embodiment, the present invention relates to compounds of the general formula (1), in which
R1 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof;
R2 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl, phenylethyl, a substituted derivative or a saturated or unsaturated, optionally substituted heterocyclic analog thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue;
U is a direct bond or an optionally substituted C1-3-alkylene group;
V is xe2x80x94NR8COxe2x80x94 or xe2x80x94NR8SO2xe2x80x94;
R8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl, phenylethyl, phenylpropyl, phenoxyethyl or a substituted derivative thereof;
A is a 1,3- or 1,4-bridging phenylene group which is unsubstituted or has at least one alkoxy residue;
B is a 1,3- or 1,4-bridging phenylene group which is unsubstituted or has at least one alkyl residue;
W is a direct bond or an optionally substituted C1-3-alkylene group;
C is 
R3 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, one of the residues (a1) to (a29) or is connected to one of R4, Y or R6, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R3 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
R4 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, one of the residues (a1) to (a29) or is connected to one of R3, Y or R6, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is CHNO2, CHCN, O or S;
Y is a direct bond or a substituted or unsubstituted methylene or methine group;
R5 is absent;
R6 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, one of the residues (a1) to (a29) or is connected to one of R3, Y or R4, if present, with formation of an optionally substituted heterocyclic 4- to 6-membered ring system which includes the nitrogen atom to which R6 is bonded, and can be saturated or unsaturated and/or can contain further heteroatoms.
Particularly preferred compounds of the general formula (1) according to this embodiment are those in which
U is a direct bond or xe2x80x94CHR7xe2x80x94;
R7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue;
A is an optionally methoxy-substituted 1,3- or 1,4-bridging phenylene group;
B is an optionally methyl-substituted 1,3- or 1,4-bridging phenylene group;
W is a direct bond;
Y is a direct bond;
and the other substituents are as defined above.
The present invention furthermore relates to a process for the preparation of the above-mentioned compounds having the general formula (1), 
which comprises the steps
a) reaction of a carboxylic acid derivative of the formula (2) 
xe2x80x83wherein
P is a conventional protective group, a solid phase used for carrying out a solid-phase reaction or R1 is as defined in claim 1;
A is a phenylene group which is 1,3- or 1,4-substituted or a thienylene group which is 2,4- or 2,5-substituted with respect to V and L and optionally has additional residues;
L is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94SCN, xe2x80x94N2+ or an organometallic residue; and the other residues are as defined above;
with a phenyl compound of the formula (3)
Mxe2x80x94Bxe2x80x94Wxe2x80x94Dxe2x80x83xe2x80x83(3)
wherein
M is xe2x80x94H, xe2x80x94I, xe2x80x94N2+, xe2x80x94COOCOBNO2 or an organometallic residue;
B is a phenylene group which is 1,3- or 1,4-substituted with respect to M and Wxe2x80x94D and optionally has additional residues;
W is as defined in claim 1;
D is xe2x80x94NO2, xe2x80x94NH2 or xe2x80x94CHO;
to give a biphenyl or thienyl-phenyl compound of the formula (4) 
where the residues are as defined above;
b) conversion of the residue D into the corresponding amino group, if D is not xe2x80x94NH2; and
c) if appropriate, derivatization of nitrogen atoms present at preferred times within the preparation process and/or the conversion of the compound obtained into the free acid and/or the conversion of the compound obtained into one of its physiologically acceptable salts by reaction with an inorganic or organic base or acid.
In the process according to the invention all steps can be carried out during the bonding of the carboxylic acid derivative of the formula (2) to a solid phase.
Furthermore, according to a preferred embodiment of the process according to the invention a carboxylic acid derivative of the formula (2), in which
L is xe2x80x94F, xe2x80x94Cl, xe2x80x94Br or xe2x80x94I
and the other residues are as defined above,
is reacted with a phenyl compound of the formula (3), in which
M is an organometallic residue;
and the other residues are as defined above,
in the presence of a palladium compound and of a phosphane.
Preferably, in the above process according to the invention a carboxylic acid derivative of the formula (2) is employed which contains a sulfonamide or carbamate group which was formed by reaction of an amino group of the corresponding precursor of the carboxylic acid derivative of the formula (2) with a sulfonyl halide or a carbamoyl halide.
It is furthermore preferred that in the above process according to the invention, in the case in which D is xe2x80x94NO2 in the compound of the formula (4), the conversion of D into an amino group is carried out in the presence of a tin(II) compound. It is furthermore preferred that in the above process according to the invention, in the case in which D is xe2x80x94CHO in the compound of the formula (4), the conversion of D into an amino group by reaction with an amine is carried out under reducing conditions.
It is moreover preferred that the compound of the formula (4) in which D is an amino group is converted into a urea or thiourea unit by a reaction of this amino group with a carbonic acid derivative or thiocarbonic acid derivative and a subsequent reaction with an amine of the formula NHR4R6, where R4 and R6 are as defined above.
The present invention furthermore relates to a pharmaceutical composition which contains at least one of the compounds defined above.
The present invention also relates to the use of the compounds described above for the production of pharmaceutical compositions having integrin-antagonistic action.
The present invention furthermore relates to the use of compounds of the general formula (1) 
wherein
R1 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x2, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22;
R2xe2x80x2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
R2xe2x80x3 is a substituted or unsubstituted alkyl, alkenyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue;
U is a direct bond or a substituted or unsubstituted alkylene group;
V is a substituted or unsubstituted alkylene group, xe2x80x94NR2xe2x80x2COxe2x80x94 or xe2x80x94NR2xe2x80x2SO2xe2x80x94;
A and B are each independently of one another a 1,3- or 1,4-bridging phenylene group or a 2,4- or 2,5-bridging thienylene group each of which may optionally have additional substituents,
W is a direct bond or a substituted or unsubstituted alkylene group;
C is a direct bond or 
R3 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl alkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R4, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R3 is bonded, and can be saturated or unsaturated and/or can contain further heteroatoms;
R4 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R3, Y, R5 or R6, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R4 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
X is CHNO2, CHCN, O, N or S;
Y is a direct bond or an optionally substituted alkylene or alkine group;
R5 is absent, or is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COR5xe2x80x2, xe2x80x94COOR5xe2x80x2, or is connected to one of R3, Y, R4 or R6, if present, with formation of an optionally substituted carbocyclic or heterocyclic ring system which includes X and can be saturated or unsaturated and/or can contain further heteroatoms;
R5xe2x80x2 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue which can be saturated or unsaturated and/or can contain further heteroatoms;
R6 is hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl or arylcarbonyl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or is connected to one of R3, R4, Y or R5, if present, with formation of an optionally substituted heterocyclic ring system which includes the nitrogen atom to which R6 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms;
and their physiologically acceptable salts and stereoisomers, for the production of a pharmaceutical composition for the inhibition of angiogenesis and/or for the therapy and prophylaxis of cancer, osteolytic diseases such as osteoporosis, arteriosclerosis, restenosis, rheumatoid arthritis and ophthalmic disorders. It is particularly preferred in this case that, for the production of the pharmaceutical composition, compounds are employed such as are defined in one of the attached claims 1 to 11.
The invention is illustrated more in detail below with reference to preferred embodiments, to which, however, it is not restricted in any way. In the description below, bivalent substituents are indicated such that their respective left end is connected to the indicated group left of the corresponding substituent in formula (1) and their respective right end is connected to the indicated group right of the corresponding substituent in formula (1). If in formula (1), for example, the residue V is xe2x80x94NR8SO2xe2x80x94, the nitrogen atom is connected to the residue U and the sulfur atom to the residue A.
The compounds according to the invention comprise, as a main structural element, a biphenyl nucleus which bridges a residue having a terminal carboxyl group with a residue including at least one nitrogen atom in the main chain, which is a constituent of an amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group which is optionally incorporated into a cyclic ring system. In the biphenyl nucleus the phenyl ring A which is located nearer to the terminal carboxyl group may optionally be replaced by a thiophene ring. In addition to one of the abovementioned residues, the biphenyl nucleus can moreover carry further substituents.
The terminal carboxyl unit can be present as a free carboxylic acid or as an ester. In the case in which the terminal carboxyl unit is esterified, in principle all carboxylic acid esters which are obtainable according to conventional processes and can be metabolized in the human body into the free carboxylic acid, such as the corresponding alkyl esters, cycloalkyl esters, aryl esters and heterocyclic analogs thereof, can be used according to the invention, wherein alkyl esters, cycloalkyl esters and aryl esters are preferred and the alcoholic residue can carry further substituents. C1-6-Alkyl esters such as the methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, isopentyl ester, neopentyl ester, hexyl ester, cyclopropyl ester, cyclopropylmethyl ester, cyclobutyl ester, cyclopentyl ester, cyclohexyl ester, or aryl esters such as the phenyl ester, benzyl ester or tolyl ester are particularly preferred.
The abovementioned esters can be employed as prodrugs for the inhibition of angiogenesis and/or the treatment of the diseases mentioned at the beginning, such as cancer, osteoporosis, arteriosclerosis, restenosis, rheumatoid arthritis or ophthalmia, since they are easily converted into the corresponding carboxylic acid in animals and humans. However, for the treatment of the abovementioned disorders the compounds of the general formula (1) according to the invention are preferably used in a form in which the terminal carboxyl unit is present as a free carboxylic acid.
For medicinal use, the compounds of the general formula (1) according to the invention can also be employed in the form of their physiologically acceptable salts. According to the invention, physiologically acceptable salts are understood as meaning nontoxic salts which in general are accessible by reaction of the compounds of the general formula (1) according to the invention with an inorganic or organic base or acid conventionally used for this purpose. Examples of preferred salts of the compounds of the general formula (1) according to the invention are the corresponding alkali metal salt, e.g. lithium, potassium or sodium salt, the corresponding alkaline earth metal salt such as the magnesium or calcium salt, a quaternary ammonium salt such as, for example, the triethylammonium salt, acetate, benzenesulfonate, benzoate, dicarbonate, disulfate, ditartrate, borate, bromide, carbonate, chloride, citrate, dihydrochloride, fumarate, gluconate, glutamate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, succinate, tartrate, tosylate and valerate, and other salts used for medicinal purposes.
The terminal carboxyl unit is connected to the biphenyl nucleus or thiophene-phenyl-nucleus by means of an alkylene chain which can optionally carry further substituents. Within certain limits, it is possible to control the biological activity of the compounds according to the invention against integrin receptors such as, in particular, the xcex1vxcex23 or xcex1vxcex25 receptor, by means of the distance between the terminal carboxyl unit and the nitrogen atom of an amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group which is located in the main chain of the residue linked to the phenyl ring B of the biphenyl nucleus or thiophene-phenyl-nucleus, where in the case in which more than one nitrogen atom is present in the main chain of the respective residue, the nitrogen atom located nearer to the phenyl ring B of the nucleus is decisive. In addition to the biphenyl nucleus or thiophene-phenyl-nucleus, preferably not more than 6 atoms should be located in the main chain between these two structural elements. However, compounds in which, additionally to the biphenyl nucleus or thiophene-phenyl-nucleus, less than 6 additional atoms are located in the main chain between the terminal carboxyl unit and the nitrogen atom of the amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group which is located in the main chain of the residue linked to the phenyl ring B of the biphenyl nucleus or thiophene-phenyl-nucleus, are more preferred. According to the present invention, particularly preferred compounds are those in which the abovementioned nitrogen atom of the amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group is bonded directly or via a xe2x80x94CH2-group to the phenyl ring B of the biphenyl nucleus or thiophene-phenyl-nucleus and, at the same time, the terminal carboxyl unit is separated from the phenyl ring A of the biphenyl nucleus or thiophene-phenyl-nucleus by two to four atoms in the main chain.
The alkylene chain which connects the terminal carboxyl group to the phenyl ring A of the biphenyl nucleus or thiophene-phenyl-nucleus can alternatively carry additional substituents on any of the carbon atoms forming the alkylene chain. These substituents can be selected from the group which consists of hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x2, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22, wherein R2xe2x80x2 can be hydrogen, a substituted or unsubstituted alkyl, alkenyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue and R2xe2x80x3 can be a substituted or unsubstituted alkyl, alkenyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue. The alkyl residue can preferably be a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl. The alkenyl residue can preferably be a C2-C6-alkenyl having one or two double bonds such as, for example vinyl, allyl, prop-1-en-yl, isopropenyl, but-1-enyl, buta-1,3-dienyl. The cycloalkyl residue can preferably be a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl. The aryl residue can preferably be phenyl, benzyl or tolyl. As an example for substituted aryl p-fluorobenzyl may be mentioned. The heterocyclic residue can preferably be pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, thiooxazole, benzofuran, quinoline, isoquinoline, pyrimidine, imidazole, thiazole, pyrazole, isoxazole and benzothiadiazole. The alkenyl residue can be a terminal or internal E- or Z-alkene unit. The abovementioned residues can alternatively carry one or more C1-6-alkyl residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, C3-7-cycloalkyl residues such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, aryl residues such as phenyl, benzyl, tolyl, naphthyl, heterocyclic residues such as pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, oxazole, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, quinoline, isoquinoline, or functional groups such as a double bond to a heteroatom such as oxygen, sulfur or nitrogen, an optionally substituted amino group, a nitro group, a halogeno group, a trifluoromethyl group, a hydroxyl group, an ether group, a sulfide group, a mercaptan group, a cyano group, an isonitrile group, an alkenyl group, an alkinyl group, an aldehyde group, a keto group, a carboxyl group, an ester group, an amide group, a sulfoxide group or a sulfone group. Furthermore, one or more saturated or unsaturated additional rings can be fused to the abovementioned cyclic residues with formation of, for example, a naphthyl, benzofuranyl, benzoxazolyl, benzothiazolyl, quinolinyl or isoquinolinyl unit or a partially or completely hydrogenated analog thereof.
Preferred substituents among those optionally located at the alkylene chain connecting the terminal carboxyl group to the phenyl ring A of the biphenyl nucleus or thiophene-phenyl-nucleus are xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x2, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22, wherein R2xe2x80x2 can be hydrogen, a substituted or unsubstituted alkyl, alkenyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue and R2xe2x80x3 can be a substituted or unsubstituted alkyl, alkenyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue. R2xe2x80x2 is preferably selected from the group which consists of hydrogen, a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl, while R2xe2x80x3 is preferably selected from the group which consists of a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a substituted C1-6-alkyl such as for example 1,1,1-trifluoro-n-but-4-yl, a C2-6-alkenyl having one double bond such as, for example allyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, such as p-fluorobenzyl, 4-ethylphenyl, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-chloro-2-trifluorophenyl, 2-trifluoromethoxy-4-bromophenyl, 2-fluoro-4-trifluoromethylphenyl, 8-quinolinyl, a group of the formula 
According to the invention, particularly preferred compounds of the general formula (1) are those in which a sulfonamide or carbamate group is located at the alkylene chain which connects the terminal carboxyl group to the phenyl ring A of the biphenyl nucleus or thiophene-phenyl-nucleus. The sulfonamide or carbamate group is preferably located in the xcex1- or xcex2-position to the terminal carboxyl group. However, more than 2 carbon atoms can also be located between the carboxyl carbon of the terminal carboxyl group and the nitrogen atom of the sulfonamide or carbamate unit. According to the present invention, the sulfonamide group, if present, particularly preferably carries a residue R2xe2x80x3 on the sulfur atom, which is selected from the group consisting of phenyl, benzyl, tolyl or a substituted derivative thereof, such as p-fluorobenzyl, xe2x80x94C6H2(CH3)3, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 8-quinolinyl or a group of the formula 
If present, the carbamate group particularly preferably carries a residue R2xe2x80x2 as an alcoholic component which is selected from the group consisting of a C1-6-alkyl residue such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, a C3-7-cycloalkyl residue such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl, and which is particularly preferably a benzyl residue.
According to a further aspect, the present invention relates to compounds of the general formula (1) in which the terminal carboxyl group is bonded to the phenyl/thienyl ring A of the biphenyl nucleus or thienyl-phenyl nucleus by means of an alkylenesulfonamide unit or an alkylenamide unit, i.e. an xe2x80x94NRSO2xe2x80x94 or xe2x80x94NRxe2x80x94COxe2x80x94 group is inserted between the alkylene chain and the phenyl/thienyl ring A of the nucleus, the phenyl/thienyl ring A of the nucleus being bonded to the sulfur atom of the sulfonamide unit or the carboxyl carbon atom of the amide unit. In accordance with the above details, the alkylene chain between the terminal carboxyl group and the sulfonamide or amide unit can in this case optionally carry further substituents, where a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, an aryl such as, for example, phenyl, benzyl, phenylethyl or tolyl, a heterocyclic residue such as pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, thiooxazole, benzofuran, quinoline, isoquinoline or pyrimidine, or a terminal or internal E- or Z-alkene unit are preferred, which can alternatively carry one or more C1-6-alkyl residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, C3-7-cycloalkyl residues such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, aryl residues such as phenyl, benzyl, tolyl, naphthyl, heterocyclic residues such as pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, thiooxazole, benzofuran, quinoline, isoquinoline or pyrimidine, or functional groups such as a double bond to a heteroatom such as oxygen, sulfur or nitrogen, an optionally substituted amino group, a nitro group, a halogeno, a hydroxyl group, an ether group, a sulfide group, a mercaptan group, a cyano group, an isonitrile group, an alkenyl group, an alkinyl group, an aldehyde group, a keto group, a carboxyl group, an ester group, an amide group, a sulfoxide group or a sulfone group. Furthermore, one or more saturated or unsaturated additional rings can be fused to the abovementioned cyclic residues with formation of, for example, a naphthyl, benzofuranyl, benzoxazolyl, benzothiazolyl, quinolinyl or isoquinolinyl unit or a partially or completely hydrogenated analog thereof.
Particularly preferred compounds according to this embodiment are those in which the alkylene chain which connects the terminal carboxyl group and the bridging sulfonamide or amide unit has a phenyl, aminophenyl, benzyl or pyridyl residue in the xcex1- or xcex2-position to the terminal carboxyl unit.
In the compounds of this aspect in which a sulfonamide or amide unit is inserted between the corresonding alkylene chain and the phenyl/thienyl ring A of the nucleus, the alkylene chain between the terminal carboxyl group and the bridging sulfonamide or amide unit should preferably comprise not more than two carbon atoms in its main chain in order that, as mentioned above, in addition to the biphenyl nucleus or thiophene-phenyl-nucleus preferably not more than 6 atoms are present between the terminal carboxyl group and the nitrogen atom of the amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group which is nearest to the phenyl ring B in the main chain of the residue linked to the phenyl ring B of the biphenyl or thienyl-phenyl nucleus.
The nitrogen atom of the bridging sulfonamide or amide unit can optionally carry a residue which is selected from the group consisting of hydrogen, a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, an aryl such as, for example, phenyl, benzyl, tolyl or a substituted derivative thereof such as, for example, phenylethyl, phenylpropyl or phenoxyethyl.
The biphenyl or thienyl-phenyl nucleus is the central structural element of the compounds according to the invention. It bridges the residue at the phenyl/thienyl ring A including the terminal carboxyl group with the residue at the phenyl ring B which comprises at least one nitrogen atom of an amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group in its main chain. Preferably, it moreover carries no further substituents. Each of the two phenyl/thienyl rings, however, can carry additional substituents. Preferably the phenyl/thienyl ring A, i.e. the ring connected directly to the residue including the terminal carboxyl group, carries one or more additional C1-6-alkyl residues such as, for example, methyl or ethyl, halogeno residues such as, for example fluoro, chloro, bromo, iodo, preferably one or two fluoro residues, alkoxy residues, preferably a C1-6-alkoxy residue such as methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy, particularly preferably one or more methoxy residues, and the phenyl ring B, i.e. the ring to which the residue including at least one nitrogen atom of an amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group in its main chain is bonded, carries one or more alkyl residues, preferably a C1-6-alkyl residue such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a C3-7-cycloalkyl residue such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and particularly preferably one or more methyl groups. In this case, the rings A and B can independently of one another carry one or more of the abovementioned additional substituents.
The two phenyl rings can be linked 1,3 or 1,4 to one another and to the residue including the terminal carboxyl group and to the residue including at least one nitrogen atom of an amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group in its main chain, i.e. the residue including the terminal carboxyl group and the phenyl ring B can be substituted in the meta- or para-position to one another at the phenyl ring A, and at the same time the phenyl ring A and the residue including at least one nitrogen atom of an amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group in its main chain can be substituted in the meta- or para-position to one another at the phenyl ring B, each combination of the abovementioned substitution patterns being possible for the biphenyl nucleus of the compounds according to the invention. In case A is a thiophene ring it can accordingly be linked 2,5 or 2,4 to ring B and to the residue including to terminal carboxy group. According to the present invention, compounds are particularly preferred whose biphenyl nucleus according to the above definition consists of a p-substituted phenyl ring A and a p-substituted phenyl ring B, a p-substituted phenyl ring A and an m-substituted phenyl ring B, an m-substituted phenyl ring A and a p-substituted phenyl ring B, or an m-substituted phenyl ring A and an m-substituted phenyl ring B. According to the present invention, compounds are particularly preferred whose biphenyl nucleus according to the above definition consists of a p-substituted phenyl ring A and an m-substituted phenyl ring B. According to another particularly preferred embodiment the nucleus consists of a 2,5-substituted thienyl ring A and a m-substituted or p-substituted phenyl ring B.
As a third structural element, in addition to the biphenyl or thienyl-phenyl nucleus and the residue including a terminal carboxyl group, the compounds according to the invention have a group which in its main chain comprises at least one nitrogen atom of an amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group. This nitrogen atom can be bonded to the phenyl ring B of the biphenyl or thienyl-phenyl nucleus directly or via an alkylene chain. This alkylene chain preferably consists of at most 4 carbon atoms in the main chain, wherein from the abovementioned considerations, in addition to the biphenyl nucleus between the terminal carboxyl group and the nitrogen atom of the amino group, amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group which is located nearest to the phenyl ring B, not more than 6 further atoms should be present. As preferred example ring B and the nitrogen atom of the amino, amide, urea, thioamide, thiourea, amidine, enamine or guanidine group are connected via a xe2x80x94CH2-group or via a direct bond. Alternatively, this alkylene chain can carry further substituents which are selected from the group consisting of hydrogen, a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, an aryl such as, for example, phenyl, benzyl or tolyl, a heterocyclic residue such as pyrrole, pyrrolidine, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, thiooxazole, benzofuran, quinoline, isoquinoline or pyrimidine, or a terminal or internal E- or Z-alkene unit, and can alternatively carry one or more C1-6-alkyl residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, cycloalkyl residues such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, aryl residues such as phenyl, benzyl, tolyl, naphthyl, indolyl, heterocyclic residues such as pyrrole, pyrrolidine, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, thiooxazole, benzofuran, quinoline, isoquinoline or pyrimidine, or functional groups such as a double bond to a heteroatom such as oxygen, sulfur or nitrogen, an optionally substituted amino group, a nitro group, a halogeno, a hydroxyl group, an ether group, a sulfide group, a mercaptan group, a cyano group, an isonitrile group, an alkenyl group, an alkinyl group, an aldehyde group, a keto group, a carboxyl group, an ester group, an amide group, a sulfoxide group or a sulfone group. Furthermore, one or more saturated or unsaturated additional rings can be fused to the abovementioned cyclic residues with formation of, for example, a naphthyl, indolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl or isoquinolinyl unit or a partially or completely hydrogenated analog thereof.
The nitrogen atom located in the main chain of the residue bonded to the phenyl ring B of the biphenyl or thienyl-phenyl nucleus, which lies nearest to the phenyl ring B, can either be a constituent of an optionally substituted amino group or can be located in direct vicinity to a xe2x80x94Cxe2x95x90O unit, xe2x80x94CONR2 unit, xe2x80x94Cxe2x95x90S unit, xe2x80x94CSNR2 unit, xe2x80x94Cxe2x95x90NR unit, xe2x80x94Cxe2x95x90CHNO2 unit, Cxe2x95x90CHCN unit or a xe2x80x94CNRNR2 unit and can thus be a constituent of an amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group.
In the case in which the nitrogen atom located in the main chain of the residue bonded to the phenyl ring B of the biphenyl nucleus, which lies nearest to the phenyl ring B, is a constituent of an amino group, it can be unsubstituted or can carry one or two substituents, i.e. can be a constituent of a primary, secondary or tertiary amino group. These substituents can be independent of one another or simultaneously hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylarnine residue, an alkylamide residue or can be bonded to one another and thus, together with the nitrogen atom to which they are bonded, form a heterocyclic ring system. In this case, substituents are preferred which are selected from the group consisting of hydrogen, a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, 2-methylbutyl, isopentyl, neopentyl or hexyl, a C1-4-perfluoroalkyl such as, for example CF3, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, an aryl such as, for example, phenyl, benzyl or tolyl, an arylcarbonyl such as for example benzoyl, a heterocyclic residue such as, for example, pyrrolidine, piperidine, piperazine, pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, imidazolidine, imidazole, oxazolidine, oxazole, thiazolidine, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, triazole, tetrazole, pyrimidine, purine, cytosine, thymine, uracil, adenine, guanine or xanthine, or a terminal or internal E- or Z-alkene unit, and can alternatively carry one or more C1-6-alkyl residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, a C1-4-perfluoroalkyl such as for example CF3, C3-7-cycloalkyl residues such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, aryl residues such as phenyl, benzyl, tolyl, naphthyl, indolyl, heterocyclic residues such as pyrrolidine, piperidine, piperazine, pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, imidazolidine, imidazole, oxazolidine, oxazole, thiazolidine, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, triazole, tetrazole, pyrimidine, purine, cytosine, thymine, uracil, adenine, guanine or xanthine, or functional groups such as a double bond to a heteroatom such as oxygen, sulfur or nitrogen, an optionally substituted amino group, a nitro group, a halogeno, a hydroxyl group, an ether group, a sulfide group, a mercaptan group, a cyano group, an isonitrile group, an alkenyl group, an alkinyl group, an aldehyde group, a keto group, a carboxyl group, an ester group, an amide group, a sulfoxide group or a sulfone group. Furthermore, one or more saturated or unsaturated additional rings can be fused to the abovementioned cyclic residues with formation of, for example, a naphthyl, indolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl or isoquinolinyl unit or a partially or completely hydrogenated analog thereof Particularly preferred substituents are those such as hydrogen, methyl, ethyl, propyl, isopropyl, 1-methylpropyl, butyl, isobutyl, t-butyl, 2-methylbutyl pentyl, isopentyl, neopentyl, hexyl, C1-4-perfluoroalkyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl, benzoyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, C1-2-perfluoroalkyl-C1-4-alkyl, 
wherein Z is hydrogen, CH3, xe2x80x94NO2 or xe2x80x94NH2.
In the case in which the two substituents at the nitrogen atom which lies nearest to the phenyl ring B are connected to one another and thus form a heterocyclic system with the nitrogen atom, the heterocyclic system formed can be selected, for example, from the following, nonexclusive list: 
where the ring systems shown can carry one or more residues which are selected from the group consisting of hydrogen, a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, an aryl such as, for example, phenyl, benzyl or tolyl, a heterocyclic residue such as, for example, pyrrolidine, piperidine, piperazine, pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, imidazolidine, imidazole, oxazolidine, oxazole, thiazolidine, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, triazole, tetrazole, pyrimidine, purine, cytosine, thymine, uracil, adenine, guanine or xanthine, or a terminal or internal E- or Z-alkene unit, and can alternatively carry one or more C1-6-alkyl residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, C3-7-cycloalkyl residues such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, aryl residues such as phenyl, benzyl, tolyl, naphthyl, indolyl, heterocyclic residues such as pyrrolidine, piperidine, piperazine, pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, imidazolidine, imidazole, oxazolidine, oxazole, thiazolidine, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, triazole, tetrazole, pyrimidine, purine, cytosine, thymine, uracil, adenine, guanine or xanthine, or functional groups such as a double bond to a heteroatom such as oxygen, sulfur or nitrogen, an optionally substituted amino group, a nitro group, a halogeno, a hydroxyl group, an ether group in particular a C1-6-alkoxy group such as for example, a methoxy gruop, a sulfide group, a mercaptan group, a cyano group, an isonitrile group, an alkenyl group, an alkinyl group, an aldehyde group, a keto group, a carboxyl group, an ester group, an amide group, a sulfoxide group or a sulfone group. Furthermore, one or more saturated or unsaturated additional rings can be fused to the abovementioned cyclic residues with formation of, for example, a naphthyl, indolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl or isoquinolinyl unit or a partially or completely hydrogenated analog thereof.
Of the ring systems shown above, the four- to six-membered ring systems are preferred.
As mentioned above, the nitrogen atom in the main chain of the residue bonded to the phenyl ring B of the biphenyl or thienyl-phenyl nucleus, which lies nearest to the phenyl ring B, can also be a constituent of one of the following preferred functional units: 
where the above list is not a conclusive enumeration of all possible structural units.
According to the invention, additionally to the abovementioned preferred structural units, analogs thereof are also included in which one or more 4- to 6-membered ring systems are fused to the heterocycle, such as, for example, the corresponding benzofused analogs of the above structural units.
In the structural units shown above, R3, R4 and R6 can each be hydrogen, a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, isobutyl, t-butyl, pentyl, 2-methylbutyl, isopentyl, neopentyl or hexyl, a C1-4-perfluoroalkyl such as, for example CF3, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl or cycloheptyl, an aryl such as, for example, phenyl, benzyl or tolyl, a C6-10-arylcarbonyl such as, for example, benzoyl, a heterocyclic residue such as, for example, pyrrolidine, piperidine, piperazine, pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, imidazolidine, imidazole, oxazolidine, oxazole, thiazolidine, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, triazole, tetrzole, pyrimidine, purine, cytosine, thymine, uracil, adenine, guanine or xanthine, or a terminal or internal E- or Z-alkene unit and can alternatively carry one or more C1-6-alkyl residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, a C1-4-perfluoroalkyl such as for example, CF3, C3-7-cycloalkyl residues such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, aryl residues such as phenyl, benzyl, tolyl, naphthyl, indolyl, heterocyclic residues such as pyrrolidine, piperidine, piperazine, pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, imidazolidine, imidazole, oxazolidine, oxazole, thiazolidine, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, triazole, tetrazole, pyrimidine, purine, cytosine, thymine, uracil, adenine, guanine or xanthine, or functional groups such as a double bond to a heteroatom such as oxygen, sulfur or nitrogen, an optionally substituted amino group, a nitro group, a halogeno, a hydroxyl group, an ether group in particular a C1-6-alkoxy group such as for example, a methoxy group, a sulfide group, a mercaptan group, a cyano group, an isonitrile group, an alkenyl group, an alkinyl group, an aldehyde group, a keto group, a carboxyl group, an ester group, an amide group, a sulfoxide group or a sulfone group. Particularly preferred substituents are those such as hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 5-methyl-2-hexyl, phenyl, benzyl, tolyl or a substituted derivative thereof, C1-4-alkylamino-C1-4-alkyl, C1-4-dialkylamnino-C1-4-alkyl, amino-C1-4-alkyl, C1-4-alkyloxy-C1-4-alkyl, or one of the abovementioned residues (a1) to (a51).
In the above structural units, R4 and R6, however, can also be bonded to one another and can form a heterocyclic ring system with the nitrogen atom to which they are bonded. Examples of these rings which can be mentioned are: 
wherein the above enumeration is nonconclusive and the ring systems formed from the connection of R4 and R6 can carry one or more residues which are selected from the group consisting of hydrogen, a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, an aryl such as, for example, phenyl, benzyl or tolyl, a heterocyclic residue such as, for example, pyrrolidine, piperidine, piperazine, pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, imidazolidine, imidazole, oxazolidine, oxazole, thiazolidine, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, triazole, tetrazole, pyrimidine, purine, cytosine, thymine, uracil, adenine, guanine or xanthine, or a terminal or internal E- or Z-alkene unit, and can alternatively carry one or more C1-6-alkyl residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, C3-7-cycloalkyl residues such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, an aryl residue such as phenyl, benzyl, tolyl, naphthyl, indolyl, heterocyclic residues such as pyrrolidine, piperidine, piperazine, pyrrole, pyridine, tetrahydrofuran, fuiran, thiophene, tetrahydrothiophene, imidazolidine, imidazole, oxazolidine, oxazole, thiazolidine, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, triazole, tetrazole, pyrimidine, purine, cytosine, thymine, uracil, adenine, guanine or xanthine, or functional groups such as a double bond to a heteroatom such as oxygen, sulfur or nitrogen, an optionally substituted amino group, a nitro group, a halogeno, a hydroxyl group, an ether group, a sulfide group, a mercaptan group, a cyano group, an isonitrile group, an alkenyl group, an alkinyl group, an aldehyde group, a keto group, a carboxyl group, an ester group, an amide group, a sulfoxide group or a sulfone group. Furthermore, one or more saturated or unsaturated additional rings can be fused to the abovementioned cyclic residues with formation of, for example, a naphthyl, indolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl unit or a partially or completely hydrogenated analog thereof. Of the ring systems formed from the connection of R4 and R6, the four- to six-membered ring systems are preferred. According to the invention, compounds wherein at least one of the residues R3, R4 or R6 is H are particularly preferred.
Furthermore, in the above structural units R5 can be hydrogen, a C1-6-alkyl residue such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, a C3-7-cycloalkyl residue such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COR5xe2x80x2 or xe2x80x94COOR5xe2x80x2, wherein R5xe2x80x2 can be a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue, which can be saturated or unsaturated and/or can contain further heteroatoms, and is preferably a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, an aryl such as, for example, phenyl, benzyl, tolyl or a substituted derivative thereof. Moreover, R5 can be connected to one of R3, Y, R4 or R6, if present, with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which includes the atom X to which R5 is bonded and can be saturated or unsaturated and/or can contain further heteroatoms.
Furthermore, in the above structural units Y can be absent or can be an alkylene or alkine unit which carries 1 to 5 carbon atoms in its main chain. According to the invention, Y, if present, preferably has a main chain consisting of one carbon atom. Y can moreover carry one or more residues which are selected from the group consisting of hydrogen, a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, an aryl such as, for example, phenyl, benzyl or tolyl, a heterocyclic residue such as, for example, pyrrolidine, piperidine, piperazine, pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, imidazolidine, imidazole, oxazolidine, oxazole, thiazolidine, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, tetrahydro-quinoline, tetrahydroisoquinoline, triazole, tetrazole, pyrimidine, purine, cytosine, thymine, uracil, adenine, guanine or xanthine, or a terminal or internal E- or Z-alkene unit, and can alternatively carry one or more C1-6-alkyl residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl or hexyl, C3-7-cycloalkyl residues such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, aryl residues such as phenyl, benzyl, tolyl, naphthyl, indolyl, heterocyclic residues such as pyrrolidine, piperidine, piperazine, pyrrole, pyridine, tetrahydrofuran, furan, thiophene, tetrahydrothiophene, imidazolidine, imidazole, oxazolidine, oxazole, thiazolidine, thiazole, thiooxazole, benzofuran, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, triazole, tetrazole, pyrimidine, purine, cytosine, thymine, uracil, adenine, guanine or xanthine, or functional groups such as a double bond to a heteroatom such as oxygen, sulfur or nitrogen, an optionally substituted amino group, a nitro group, a halogeno, a hydroxyl group, an ether group, a sulfide group, a mercaptan group, a cyano group, an isonitrile group, an alkenyl group, an alkinyl group, an aldehyde group, a keto group, a carboxyl group, an ester group, an amide group, a sulfoxide group or a sulfone group. Furthermore, one or more saturated or unsaturated additional rings can be fused to the abovementioned cyclic residues with formation of, for example, a naphthyl, indolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl or isoquinolinyl unit or a partially or completely hydrogenated analog thereof. Moreover Y can be connected to one of R3, R4, R5 or R6, if present, with formation of an optionally substituted carbocyclic or heterocyclic 4- to 6-membered ring system which can be saturated or unsaturated and/or can contain further hetero atoms.
According to the invention, particularly preferred compounds of the general formula (1) are those in which the nitrogen atom located in the main chain of the residue bonded to the phenyl ring B, which lies nearest to the phenyl ring B, is a constituent of a urea or thiourea unit. In this case, particularly preferred compounds of the general formula (1) are those in which a urea or thiourea unit is bonded directly to the phenyl ring B of the biphenyl nucleus.
Furthermore particularly preferred compounds of the general formula (1) are those in which the nitrogen atom located in the main chain of the residue bonded to the phenyl ring B, which lies nearest to the phenyl ring B is a constituent of an amino group which is bonded via a methylene group to ring B. The amino group can preferably be substituted by one of the residues (a1) to (a51).
The present invention comprises both the individual enantiomers or diastereomers and the corresponding racemates, diastereomer mixtures and salts of the compounds defined in claim 1. In addition, all possible tautomeric forms of the compounds described above are also included according to the present invention. The present invention furthermore comprises both the pure E and Z isomers of the compounds of the general formula (1) and their E/Z mixtures in all ratios. The diastereomer mixtures or E/Z mixtures can be separated into the individual isomers by chromatographic procedures. The racemates can be separated into the respective enantiomers by chromatographic procedures on chiral phases or by resolution of racemates.
The compounds described above can be prepared from commercially available starting compounds. The essential steps of the preparation process according to the invention are the reaction of a carboxylic acid, whose carboxyl group is protected and which has at least one aryl or thienyl group provided with a residue accessible to an aryl-aryl coupling reaction, with a phenyl compound having at least one residue accessible to an aryl-aryl coupling reaction, which furthermore has a residue D which is an amino group or can be converted into an amino group in a simple manner, and the conversion of the residue D into the corresponding amino group if it is not already an amino group. The derivatization of nitrogen atoms present in the molecule at preferred times within the preparation process and/or the conversion of the compound obtained into the free acid and/or the conversion of the compound obtained into one of its physiologically acceptable salts by reaction with an inorganic or organic acid or base can be included as further process steps.
The carboxylic acids to be employed as starting compounds are either commercially available or are easily accessible by standard chemical processes, such as are known to any person skilled in the art and are described in standard textbooks such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme-Verlag, Stuttgart.
According to a preferred embodiment, starting materials used in the process according to the invention for the preparation of compounds of the general formula (1) are the following carboxylic acid derivatives: 
Analogously for the thienyl-phenyl compounds, the corresponding thienyl-derivative ist used.
For the preparation process according to the invention, the carboxyl group is in this case blocked by a conventional protective group P. Protective groups of this type are known to the person skilled in the art and do not have to be expressly mentioned here. The carboxyl group is particularly preferably esterified, P being a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, an aryl such as, for example, phenyl, benzyl, tolyl or a substituted derivative thereof. The preparation process according to the invention for the compounds of the general formula (1) can be carried out on a solid phase in order to achieve a process implementation which is as economical as possible. In this case, the carboxyl residue can be bonded to any solid phase conventionally used for reactions of this type. According to the invention, the solid phase used is particularly preferably a polystyrene resin and in particular a commercially available Wang polystyrene resin. According to the present preferred embodiment, R2 can be as described above and V can be an optionally substituted C1-5-alkylene group. Thus the starting compounds of this preferred embodiment can be interpreted as derivatives of propanoic acid, butanoic acid, pentanoic acid, hexanoic acid or heptanoic acid. In the a-position to the carboxyl group, these carboxylic acid derivatives can have a substituent such as, for example, hydrogen, a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, an aryl such as, for example, phenyl, benzyl, tolyl or a substituted derivative thereof, an optionally substituted alkenyl residue, an optionally substituted alkinyl residue, xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x3, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22. The alkyl and cycloalkyl residues and the benzyl residue can be introduced by reaction of the ester of the starting compounds with the appropriate alkyl, cycloalkyl or benzyl halides in basic medium, if the corresponding derivatives are not commercially available. The alkinyl residue can be introduced, for example, by reaction of the xcex1-bromo ester of the present starting compound with an appropriate acetylide anion. In the case of the phenyl residue, of the alkenyl residue and of the nitrogen-containing substituents, the starting materials used are preferably the corresponding xcex1-phenyl- or xcex1-aminocarboxylic acid derivatives and, if necessary, the other substituents at the xcex1xe2x80x94C atom to the terminal carboxyl group are introduced via the appropriate alkyl halide. The above reactions and their implementation are well known to the person skilled in the art and are described in detail in standard textbooks such as, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart.
For the introduction of a substituent into the xcex2-position relative to the carboxyl group, the possibility that suggests itself, for example, is to start from the corresponding xcex1,xcex2-unsaturated carboxylic acid derivatives and to react these with the respective alkyl or cycloalkyl cuprates in the sense of a Michael addition. xcex2-substituted derivatives are also accesible via the condensation of a derivative of malonic acid with an aldehyde or a keton. Subsequently, if desired, another substituent can be introduced into the xcex1-position relative to the carboxyl group as described above. These reactions and their implementation are also well known to the person skilled in the art and are described in detail in standard textbooks such as, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart.
The residues xe2x80x94NR2xe2x80x2SO2R2xe2x80x3, xe2x80x94NR2xe2x80x2COOR2xe2x80x2, xe2x80x94NR2xe2x80x2COR2xe2x80x2, xe2x80x94NR2xe2x80x2CONR2xe2x80x22 or xe2x80x94NR2xe2x80x2CSNR2xe2x80x22 preferably found in the xcex1- or xcex2-position relative to the carboxyl group are preferably prepared from the respective xcex1- or xcex2-amino acid. The xcex1-amino acids used according to the invention are commercially available, for example, from Novabiochem or Bachem. The xcex2-amino acids can in some cases likewise be obtained from these companies or can be prepared according to the procedures of T. B. Johnson, Journal of the American Chemical Society, 1936, 58, or of V. A. Soloshonok, Tetrahedron Assymetry, 1995, 1601. These amino acids can be converted into the desired carboxyl-protected amino acid derivative, for example, by protection of the amino group, subsequent protection of the carboxylic acid unit and subsequent deprotection of the amino group. Protective groups which can be used in this case for the amino group are all groups known for this purpose. According to the invention, the use of a 9-fluorenylmethoxycarbonyl group (FMOC) as a protective group for the amino unit is particularly preferred. The carboxylic acid group is protected or derivatized as described above. The carboxyl-protected xcex1- or xcex2-amino acids thus accessible are reacted with a suitable sulfonating, carbamoylating or acylating reagent in order to obtain the corresponding sulfonamide, carbamate or amide derivatives. The sulfonating reagent is preferably a sulfonyl chloride of the formula R2xe2x80x3xe2x80x94SO2Cl or a chloroformiate of the formula R2xe2x80x2xe2x80x94OCOCl, wherein R2xe2x80x2 is preferably selected from the group which consists of hydrogen, a C1-6-alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a C3-7-cycloalkyl such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, tolyl or a substituted derivative thereof as, for example, 2-chlorophenyl, 2-methoxyphenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dichlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-trifluoromethyl phenyl, while R2xe2x80x3 is a C1-10-alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or campher-10-yl, an aryl such as phenyl, benzyl, tolyl, mesityl or substituted derivatives of these such as 2-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, campher-10-yl, 4-methoxyphenyl, 4-t-butylphenyl, 2,5-dimethylphenyl, 3-chlorophenyl, 2-methoxy-5-methylphenyl, 2,3,5,6-tetramethylphenyl, 2,3-dichlorophenyl, 2,6-dichlorophenyl, 2-naphthyl, 3-trifluoromethylphenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-chloro-6-methylphenyl, 2-chloro-4-fluorophenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-chloro-6-methoxyphenyl, 2-trifluoromethylphenyl, 2-alkylsulfonylphenyl, 2-arylsulfonylphenyl, 3-(N-acetyl-6-methoxy)anilino, 2-methoxycarbonylphenyl, 4-N-acetylphenyl, 4-ethylphenyl, 3-chloro-4-fluorphenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 1-naphthyl, 4-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, or 8-quinolinyl, or a heterocyclic analog of the abovementioned cyclic residues. Particularly preferably, R2xe2x80x3 is a mesityl residue, a benzyl residue, a 2-chlorophenyl residue, a 4-chlorophenyl residue, a 2,5-dichlorophenyl residue, a 2,6-dichlorophenyl residue, a 4-trifluoromethylphenyl residue, a campher-10-yl residue or a group of the formula 
Instead of the abovementioned sulfonyl or carbamoyl chlorides, the corresponding fluorides, bromides or iodides can also be employed. As an acylating reagent, the appropriate carboxylic acid halides or carboxylic acid anhydrides are reacted with the amino group, the appropriate C1-6-alkyl- such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, t-butyl-, pentyl-, isopentyl-, neopentyl-, hexyl-, C3-7-cycloalkyl- such as cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-, aryl- such as phenyl-, benzyl- or tolylcarboxylic acid chlorides or substituted derivatives thereof being preferred according to the invention. For the preparation of the urea or thiourea residues, the amino group is preferably first reacted with a carbonic acid or thiocarbonic acid derivative such as a chloroformic acid ester or thiophosgene and then with a suitable amine NHR2xe2x80x22. The above reactions and their implementation are well known to the person skilled in the art and are described in detail in standard textbooks such as, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart.
The starting compounds to be employed according to the above preferred embodiment have a terminal phenyl unit which must carry at least one substituent L. This substituent L must be substitutable by another phenyl group by means of one of the known aryl-aryl coupling procedures. According to the present invention, L can be xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94SCN, xe2x80x94N2+ or an organometaillic residue. Preferred organometallic residues which may be mentioned are, for example, a magnesium, copper, boron, tin, lithium or lithium cuprate residue.
Additionally to the residues V and L, the terminal phenyl unit can have one or more further substituents, preferably one or more alkoxy residues, particularly preferably one or more methoxy residues.
If the corresponding starting compounds are not commercially available, the terminal phenyl unit can be connected to the appropriate carboxylic acid derivative by standard processes such as, for example, a Friedel-Crafts alkylation, Friedel-Crafts acylation or by organometallic synthesis procedures such as, for example, a palladium-assisted coupling, after which, if appropriate, further derivatization steps follow which are known to the person skilled in the art and described in detail in standard textbooks such as, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart.
The terminal phenyl unit can be 1,3- or 1,4-substituted with respect to the residues V and L. Each of these isomers, if not commercially available, is accessible in a manner known to the person skilled in the art.
According to a further preferred embodiment, starting materials used in the process according to the invention for the preparation of compounds of the general formula (1) are the following carboxylic acid derivatives: 
For the preparation of the thienyl-phenyl-compounds the corresponding thienyl-derivatives are used as stating materials.
In this case, P and R2 are as described above and can be introduced in the manner explained above if they are not already contained in the commercial starting compound. U represents an optionally substituted alkylene group and preferably an optionally substituted C1-3-alkylene group. With respect to the possible substituents at U, reference is made to the above explanations for the compounds according to the invention.
For example, in the case in which U is an optionally substituted methylene group, the optionally additionally substituted 3-aminopropanoic acid is used as a starting material for the preparation of the compound shown above and this is reacted with an arylsulfonyl halide, preferably an arylsulfonyl chloride. The arylsulfonyl chloride is selected in accordance with the desired presence and position of the residues L and OAlk, L having the same meaning as described above and OAlk representing one or more alkoxy residues, preferably one or more methoxy residues. The arylsulfonyl halides preferred according to the invention are commercially available or can be prepared by standard reactions familiar to the person skilled in the art. The above reactions and their implementation are well known to the person skilled in the art and are described in detail in standard textbooks such as, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart.
In all embodiments according to the invention, the biphenyl or thienyl-phenyl nucleus is generated by means of an aryl-aryl coupling. Formally, in this case the residue L at the terminal phenyl/thienyl group of the carboxylic acid derivative serving as a starting compound is replaced by a phenyl compound of the following formula
Mxe2x80x94Bxe2x80x94Wxe2x80x94Dxe2x80x83xe2x80x83(3)
wherein
M is xe2x80x94H, xe2x80x94I, xe2x80x94N2+, xe2x80x94COOCOBNO2 or an organometallic residue;
B is a phenylene group which is 1,3- or 1,4-substituted with respect to M and Wxe2x80x94D and optionally has additional residues;
W is as defined in claim 1;
D is xe2x80x94NO2, xe2x80x94NH2 or xe2x80x94CHO;
Possible coupling reactions are, for example, the reaction of two unsubstituted phenyl groups (i.e. L and M are hydrogen) in the presence of AlCl3 and an acid (Scholl reaction), the coupling of the two phenyl iodides in the presence of copper (Ullmann reaction), the reaction of the unsubstituted carboxylic acid derivative with a phenyldiazonium compound under basic conditions (Gomberg-Bachmann reaction) or coupling with participation of organometallic reagents. In this connection, the coupling of two phenyl Grignard compounds in the presence of thallium bromide, the coupling of two organoboron compounds in the presence of silver nitrate and sodium hydroxide, the reaction of a diphenyllithium cuprate in the presence of oxygen and palladium-assisted couplings of a phenyl halide with an organometallic phenyl compound deserve mention. The implementation of these reactions is described in detail in standard textbooks such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart. The choice of the coupling reaction depends on the presence of possibly interfering or sensitive substituents in the reactants. For the preferred compounds according to the invention, however, it has proven particularly advantageous to generate the biphenyl nucleus by coupling of a phenyl halide with an organometallic phenyl compound in the presence of a palladium compound, for example a Pd(0), a Pd(II) or a Pd(IV) compound, and of a phosphane such as triphenylphosphane.
The thienyl-phenyl compounds can be prepared in analogous manner according to the methods described above.
The phenyl/thienyl halide used in this case can be the corresponding phenyl/thienyl fluoride, chloride, bromide or iodide, the corresponding bromide being particularly preferred. The organometallic phenyl compound used is preferably a substance in which a metallic element such as, for example, zinc, magnesium, boron, lithium, copper, tin or another element conventionally used for this purpose is bonded directly to the aryl ring. According to the invention, organoboron compounds are particularly preferred. Further substituents can be bonded to the aryl ring additionally to the residue xe2x80x94Wxe2x80x94D and the metallic element. Preferably, these substituents are one or more alkyl residues, preferably a C1-6-alkyl residue such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, a C3-7-cycloalkyl residue such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and particularly preferably one or more methyl groups. If W is present, i.e. the residue D is bonded to the phenyl ring B via an optionally substituted alkylene group, the length of the main chain of this alkylene group must be selected for reasons described above such that no more than 6 atoms additionally to the biphenyl or thienyl-phenyl nucleus are present in the resulting compound of the formula (4) between the terminal carboxyl unit and the residue D.
Particularly preferred aryl reagents according to the invention are 3-nitrobenzeneboronic acid, 3-formylbenzeneboronic acid or 3-aminobenzeneboronic acid.
The residue D thus introduced into the compound, if it is not already an amino group, is converted into an amino group. In the case in which D is a nitro group, this is reduced to the corresponding amino group by conventional reductancts such as, for example, tin chloride. In the case in which D is an aldehyde group, the conversion into the amino group is carried out by reaction with an amine under reducing conditions, for example in the presence of an ortho ester and of a reductant such as a metal hydride, for example a boron hydride. The amino group thus formed can subsequently be derivatized, for example by reaction with, for example, alkyl or cycloalkyl halides. With respect to the preferred substituents on the nitrogen atom which can be introduced in this way, reference is made to the above description of the compounds according to the invention.
The amines can be converted into the squaric acid monoamides which in turn can be functionalised to the corresponding squaric acid diamides by treating with amines. The amines can further be converted into the 1,1-diaminonitroethylenes by treatment with an appropriate alkylating agent, preferrabyl 1,1-dithiomethyl-2-nitroethylene and subsequent conversion with another amine. The amines can further be converted into the 2,3-diaminothiadiazoles by treatment with an appropriate alkylating agent, preferrabyl 3,4-bismethythio-1,2,5 thiadiazole-1 oxide and subsequent conversion with another amine. Finally the amines can be transformed into the diamino-cyanoguanidines by treatment with an appropriate alkylating agent, preferrably cyanimidodithiocarbonate dimethyl ester and subsequent conversion with another amine.
The thioureas can be converted to heterocycles such as benzimidazoles by cyclisation of a suited thiourea with a desulflirizing agent such as HgO. Thiazoles can be generated by alkylation with suitable alkylating agents preferrably 1,2-dichloroethylethylether, or 2-chloro-1,1-bisethoxyethane. The imidazoles can be obtained from the thioureas by alkylating with methyl iodide, followed by treatment with 1,1-diethoxy-2aminoethane and subsequent acid-mediated ring closure.
According to a preferred embodiment of the present invention, the synthesis of the compounds according to the invention is carried out on a solid phase such as a polystyrene resin, particularly preferably a commercially available Wang polystyrene resin. In this case, the resin is first swollen in a solvent such as dimethylformamide (DMF). The carboxylic acid serving as a starting compound is then bonded to the resin by standard procedures. For example, the bonding of the carboxylic acid to the resin can be carried out in the presence of a base such as pyridine and a reagent activating the carboxyl unit, such as an acid halide, for example dichlorobenzoyl chloride, in a solvent such as dimethylformamide (DMF). However, other reagents conventionally used for this purpose can also be employed. The reaction mixture is stirred at room temperature and normal pressure for at least 2 hours, preferably 12 hours, particularly preferably approximately 24 hours, the carboxylic acid being employed in an excess, preferably in a two- to three-fold excess, with respect to the loading of the solid phase.
After removal of possibly unreacted reagents, if desired, a derivatization of the carboxylic acid bonded to the resin can be carried out without this needing to be separated from the resin beforehand. According to a preferred embodiment according to the invention, an amino acid whose amino group is protected is bonded to the solid phase, for example as described above, and after liberation of the amino group a substituent is then introduced onto the latter. Preferably, the amino group is sulfonylated or carbamoylated. For this purpose, the amino acid bonded to the solid phase is treated with an excess of a solution of the appropriate sulfonylating or carbamoylating agent, preferably a two- to four-fold excess, particularly preferably an approximately three-fold excess, in a solvent such as, for example, tetrahydrofuran (THF) in the presence of an auxiliary base such as diisopropylethylamine and the reaction mixture is stirred at room temperature and normal pressure for at least 2 hours, preferably 12 hours, particularly preferably approximately 24 hours. The sulfonamide or carbamate obtained does not have to be removed from the resin, but can be immediately reacted further after removal of unreacted reactants which may possibly be present.
The aryl-aryl coupling is preferably carried out according to the invention by treating the carboxylic acid bonded to the solid phase, which is optionally derivatized, for example sulfonylated or carbamoylated as described above, in aqueous medium in the presence of a base such as sodium carbonate with the appropriate aryl coupling reagent of the formula (3) and a catalyst conventionally used for this purpose, for example a palladium(II) salt, preferably bis-(triphenylphosphane)-palladium(II) chloride in combination with triphenylphosphane. An approximately 3- to 8-fold, preferably an approximately 4- to 6-fold, excess of the aryl coupling agent, which according to the invention is in particular 3-nitrobenzeneboronic acid, 3-formylbenzeneboronic acid or 3-aminobenzenboronic acid, and catalytically active amounts of the palladium compound, for example approximately 10 times lower than the amount of the carboxylic acid, is preferably employed in this case and, after stirring briefly at room temperature, for example for 5 to 10 minutes, the reaction mixture is heated for approximately 2-24 hours, preferably 6-24 hours and particularly preferably 12-24 hours, to a temperature in the range from 40 to 110xc2x0 C., preferably 50 to 100xc2x0 C. and particularly preferably 60 to 90xc2x0 C. The biphenyl compound obtained can immediately be reacted further without purification after unreacted reactants which may be present are removed by washing with an acidic solution, for example a hydrochloric acid solution.
If the residue D is a nitro group, its conversion into an amino group is preferably carried out according to the invention by addition of a customary reductant such as tin(II) chloride to the intermediate bonded to the solid phase and obtained as above, if appropriate in the presence of solvents such as N-methylpyrrolidone (NMP), by stirring the reaction mixture at room temperature and normal pressure for at least 2 hours, preferably 12 hours, particularly preferably approximately 24 hours.
If the residue D is an aldehyde group, its conversion into an amino group is carried out by reductive amination. For this purpose, the intermediate bonded to the solid phase and obtained as above is treated with an approximately 3- to 6-fold, preferably approximately 4- to 5-fold, excess of an amine, optionally in the presence of diisopropylethylamine, and of an approximately 6- to 10-fold excess of ortho ester. After stirring at room temperature for several hours, preferably 1 to 3 hours, an approximately 3- to 6-fold, preferably 4- to 5-fold, excess of an acetic acid solution of a metal hydride such as, for example, tetrabutylammonium borohydride is added to the reaction mixture and it is stirred again for several hours, preferably 12-24 hours, at room temperature.
The product obtained above can optionally be reacted further by derivatization of the residue D of the compound of the formula (4) representing an amino group or an introduction of further substituents onto nitrogen atoms present in the molecule or directly removed from the resin. Removal from the resin is carried out in a conventional manner in acidic medium. After removal of solvent which may be present, the product separated off from the resin can be purified by known purification procedures such as, for example, chromatographic procedures.
The residue D of the compound of the formula (4) representing an amino group can furthermore be converted into an amide group, urea group, thioamide group, thiourea group, amidine group, enamine group or guanidine group. These structural units can be prepared by the standard reactions familiar to the person skilled in the art, such as are described, for example, in Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart.
It is particularly preferred according to the invention to convert the residue D of the compound of the formula (4) representing an amino group into a urea or thiourea unit. For this purpose, the above amino group of the carboxylic acid bonded to the solid phase is first preferably reacted with a 2- to 5-fold, preferably 3- to 4-fold, excess of a carbonic acid ester or thiocarbonic acid ester derivative in an inert solvent such as tetrahydrofuran (THF), dichloromethane or a mixture of the two (preferably a 1:1 mixture) at room temperature and with stirring for approximately 1 hour, preferably approximately 45 minutes. The carbonic acid ester or thiocarbonic acid ester derivative employed is preferably phosgene, triphosgene, thiophosgene or chloroformic acid esters, commercially obtainable chloroformic acid esters being preferred for the preparation of the urea derivatives and thiophosgene for the preparation of the thiourea derivatives.
The carbamates or isothiocyanates formed in this way are convertible into the corresponding urea and thiourea derivatives by reaction with suitable amines. Amines which can be used are substances of the formula HNRRxe2x80x2, wherein R and Rxe2x80x2 independently of one another or simultaneously are hydrogen, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue, a saturated or unsaturated, optionally substituted heterocyclic residue, an alkylamine residue, an alkylamide residue or are connected to one another and together with the nitrogen atom can form an optionally substituted heterocyclic ring system which can be saturated or unsaturated and/or can contain further heteroatoms. With respect to the preferred residues at the amine, reference is made to the above description of the compounds according to the invention. According to the invention, the carbamate or isothiocyanate bonded to a solid phase is preferably reacted with a distinct excess of amine, preferably a 3- to 10-fold excess and particularly preferably a 5- to 10-fold excess, at room temperature with stirring for approximately 1 to 5 hours, preferably aproximately 2 to 3 hours, in the presence of an auxiliary base such as diisopropylethylamine in an inert solvent such as dimethylformamide (DMF).
According to another preferred embodiment of the present invention, the synthesis of the compounds according to the invention is carried out with a commercially available amino functionalized ester serving as a protected carboxylic starting compound. Preferably, the amino group is sulfonylated or carbamoylated. For this purpose, the amino ester and the appropriate sulfonylating or carbamoylating agent are dissolved in a solvent such as, for example, dichloromethane and an auxilliary base such as pyridine or triethylamin is added at 0xc2x0 C. The mixture is stirred at 0xc2x0 C. for 1 hour and then at room temperature overnight. The reaction mixture is washed with an aqueous acid such as, for example, aq 1N HCl, brine and water and dried. The concentrated organic solutions are recrystallized in a solvent such as, for example, acetic acid ethyl ester/petroleum ether or if necessary are purified by chromatography over silica, using cyclohexane/ethyl acetate as the solvent.
The aryl-aryl coupling is preferably carried out according to the invention by treating the ester, winch is optionally derivatized, for example sulfonylated or carbamoylated as described above, in an appropriate solvent such as, for example, 1,2 dimethoxyethane in the present of a base such as aqueous sodium carbonate with the appropriate aryl coupling reagent of the formula (3) such as, for example, 3-aminobenzeneboronic acid or 3-formylbenzeneboronic acid and a catalyst conventionally used for this purpose, for example a palladium(II) salt, preferably bis(triphenylphosphane)-palladium(II) chloride. The mixture is heated to reflux for 3 hours and then cooled to room temperature. After dilution with ethyl acetate, the mixture is successiveley washed with 5% aqueous sodium dihydrogenphosphate, water and brine and dried. After removal of the solvent the crude product is purified over silica, using cyclohexane/ethyl acetate as the solvent.
If the residue D is an aldehyde group, its conversion into an amino group is carried out by reductive amination. For this purpose, the intermediate obtained as above is treated with an amine in the presence of acetic acid and methanol. After stirring at room temperature for 5 hours a metal hydride such as, for example, sodium cyanoborohydride is added. The mixture is stirred overnight and then treated with aqueous 2M hydrochloric acid. After removal of most of the solvent the residue is neutralized with 2M aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer is washed with brine and dried. The solvent is removed and the crude product is purified over silica with dichloromethane/ethyl acetate as the solvent.
According to another preferred embodiment of the present invention the residue D of the compound of the formula (4) representing an amino group is converted into the squaric acid monoamide which in turn can be functionalised to the corresponding squaric acid diamides by treating with amines. The amino group can further be converted into the 1,1-diaminonitroethylenes by treatment with an appropriate alkylating agent, preferrabyl 1,1-dithiomethyl-2-nitroethylene and subsequent conversion with another amine. The amino group can further be converted into the 2,3-diaminothiadiazoles by treatment with an appropriate alkylating agent, preferrabyl 3,4-bismethythio-1,2,5-thiadiazole-1-oxide and subsequent conversion with another amine. The amino group can be transformed into the diaminocyanoguanidines by treatment with an appropriate alkylating agent, preferrably cyanimidodithiocarbonate dimethyl ester and subsequent conversion with another amine. The thioureas can be converted into heterocycles such as benzimidazoles by cyclisation of a suited thiourea with a desulfurizing agent such as HgO. Thiazoles can be generated by alkylation with suitable alkylating agents preferrably 1,2-dichloroethylethylether, or 2-chloro-1,1-bisethoxyethane. The imidazoles can be obtained from the thioureas by alkylating with iodomethane, followed by treatment with 1,1-diethoxy-2-aminoethane and subsequent acid mediated ring closure.
The compounds obtained according to the procedures explained above can furthermore be derivatized by continuing substitution of nitrogen atoms present at preferred positions in the preparation procedure and/or conversion of the compound obtained into the free acid and/or its physiologically acceptable salts. Suitable alkylating agents in this step are reagents conventionally used for this purpose, with which, for example, a substituted or unsubstituted alkyl or cycloalkyl residue, a substituted or unsubstituted aryl residue or a saturated or unsaturated, optionally substituted heterocyclic residue can be bonded to the appropriate nitrogen atom. With respect to the substituents preferably bonded to the respective nitrogen atoms, reference is made to the above description of the compounds according to the invention. The above reactions and their implementation are well known to the person skilled in the art and are described in detail in standard textbooks such as, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart.
The ester derivatives according to the invention can be converted into the corresponding free carboxylic acids in a conventional manner, such as, for example, by basic hydrolysis with a solution of aqueous sodium hydroxide or lithium hydroxide in tetrahydrofuran (THF) or dimethoxyethane and following acidification with acetic acid or aqueous HCl.
If desired, the compounds according to the invention can be converted into their physiologically acceptable salts. This can be carried out either by reaction with an organic or inorganic base such as, for example, an alkali metal hydroxide or alkaline earth metal hydroxide such as KOH, NaOH, LiOH, Mg(OH)2 or Ca(OH)2, by means of which the terminal carboxyl group is deprotonated and the corresponding carboxylate is formed, or by reaction with an organic or inorganic acid such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, mandelic acid, oleic acid, linoleic acid or p-toluenesulfonic acid, by means of which one or more of the nitrogen atoms present are protonated.
The steps of the preparation process according to the invention described above can be carried out in a normal atmosphere, i.e. in air, and without the use of absolute, i.e. essentially anhydrous, solvents.
The compounds according to the invention exhibit a very good antagonistic action against integrin receptors, in particular the xcex1vxcex23 receptor or the xcex1vxcex25 receptor. This makes them suitable for use in pharmaceutical compositions, in particular for the treatment and prophylaxis of arteriosclerosis, restenosis, osteolytic disorders such as osteoporosis, cancer and ophthalmic diseases. Furthermore they are suitable for the reduction and inhibition of angiogenesis and consequently they are suitable for the prophylaxis and treatment of conditions and diseases such as cancer or rheumatoid arthritis.
The compounds according to the invention can be used as active compound components for the production of pharmaceutical compositions against the abovementioned diseases. For this purpose, they can be converted into the customary formulations such as tablets, coated tablets, aerosols, pills, granules, syrups, emulsions, suspensions and solutions using inert, nontoxic, pharmaceutically suitable excipients or solvents. Preferably, the compounds according to the invention are in this case used in such an amount that their concentration in the total mixture is approximately 0.5 to approximately 90% by weight, the concentration being dependent, inter alia, on the corresponding indication of the pharmaceutical composition.
The abovementioned formulations are prepared, for example, by extending the active compounds with solvents and/or excipients having the above properties, where, if appropriate, emulsifier or dispersant and, in the case of water as a solvent, alternatively an organic solvent additionally has to be added.
The pharmaceutical compositions according to the invention can be administered in a customary manner.